Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated cation channels in the central nervous system (CNS) and the peripheral nervous system (PNS). The nAChRs serve a wide range of physiological functions, and have been implicated in a number of pathological processes and pharmacological effects of nicotinic drugs. Many of the important in vivo effects of nicotine in the central nervous system (CNS) are mediated mainly by the desensitization of nAChRs, specifically α4β2 nAChRs, which are the major nAChR subtype in the CNS and the one most clearly affected (up-regulated) by chronic administration of nicotine in rats and mice and by smoking in humans.
The actions of nicotine and other nicotinic agonists to activate and then desensitize nAChRs have been known for more than 100 years and conceptualized for more than 50 years. A fundamental question about nicotinic cholinergic signaling in the CNS and PNS is how each of these two opposite actions contributes to the overall pharmacological effects of nicotinic ligands. It is widely accepted that activation of nAChRs plays important roles in mediating the effects of nicotinic ligands, but many lines of evidence reported in recent years support the notion that the desensitization of nAChRs is also an important mechanism mediating effects of nicotinic drugs. In addition, it is important to note that strong agonist activities of nicotinic drugs on some nAChR subtypes (α3β4 subtype, for example) are responsible for some adverse effects.
Sazetidine-A (Saz-A) is a nAChR ligand which is a selective α4β2 nAChR desensitizer. U.S. Pat. No. 8,030,300 (incorporated by reference). Its major in vitro effect is to desensitize α4β2 nAChRs without affecting either α3β4 or α7 nAChRs. Saz-A shows strong in vivo effects in animal models, including analgesia, reduction in nicotine self-administration, reduction in alcohol intake, antidepressant-like activity, and reversal of attentional impairment. The discovery of novel subtype selective nicotinic ligands that have low efficacy for activation but high potency for desensitization represents an important long-term goal. Effective subtype selective nAChR ligands must also have better chemical and pharmacological properties than those of classical nicotinic ligands and currently marketed nicotinic drugs.